Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD

Sixteen patients receiving maintenance hemodialysis will be randomized to 26 weeks of therapy with combination hydralazine/isosorbide dinitrate or placebo. Study medications will be titrated to goal dose during the first 4 weeks and maintained at goal dose (as tolerated) between weeks 4-26. A final study visit to assess symptoms after drug discontinuation will occur 4 weeks after drug discontinuation.

Study duration-Maximum of 32 weeks with 26 weeks of active therapy.

Efficacy Measures -Tissue Doppler echocardiography and myocardial perfusion scanning using radioactive NH3 PET will be assessed at weeks 0 and 26.

Safety Measures-Adverse events rates including inter- and intra-dialytic hypotension, ,cardiovascular death and gastrointestinal symptoms will be assessed throughout the duration of the study.

Inclusion criteria

• Maintenance hemodialysis therapy for end-stage renal disease
• Age 18-85 years
• ≥ 90 days since dialysis initiation
• Ability to provide informed consent
• Pre-dialysis seated systolic blood pressure measurements must be ≥ 120 mm Hg in the 2 weeks before enrollment and on the day of randomization.

Exclusion criteria

• Serum potassium ≥6.5 mEq/L within 2 months prior to screening
• Unscheduled dialysis for hyperkalemia within the 3 months prior to screening
• Hypotension defined as pre-dialysis SBP <100 mm Hg (seated measurement) within 4 weeks prior to enrollment
• Recurrent intra-dialytic hypotension, defined as systolic blood pressure <80 mm Hg during ≥3 dialysis sessions per 30-day rolling period or treatment for either hypotension or symptoms of hypotension if systolic blood pressure is < 100 mm Hg during ≥3 dialysis sessions per 30-day rolling period.
• Mitral valve repair or replacement
• Severe mitral valve disease by echocardiography, coronary angiography or cardiac magnetic resonance imaging
• Prior coronary artery bypass graft
• Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 6 months
• Expected survival < 6 months
• Allergy to study medications (ISD, HY, adenosine/diprimidole)
• Active use of sildenafil, vardenafil or tadalafil
• History of severe aortic stenosis or other cause of LV outflow obstruction
• Pregnancy, anticipated pregnancy, or breastfeeding, confirmed by serum pregnancy test on the day of PET scan
• Incarceration
• Participation in another intervention study
• Use of monoamine oxidase inhibitors
• Contraindication to adenosine including

• 2nd or 3rd degree heart block, sick sinus syndrome or symptomatic bradycardia (without a functioning pacemaker)
• moderate or severe asthma
• chronic obstructive pulmonary disease
• Active use of any of the study medications unless participant and physician willing to discontinue prior to enrollment.